The RhoJ-BAD signaling network: An Achilles' heel for BRAF mutant melanomas.

Authors

Rolando Ruiz
Sohail Jahid
Melissa Harris
Diego M Marzese, Department of Translational Molecular Medicine, Division Molecular Oncology, John Wayne Cancer Institute (JWCI), Providence Saint John's Health Center, Santa Monica, CA, United States of America.
Francisco Espitia
Priya Vasudeva
Chi-Fen Chen
Sebastien de Feraudy
Jie Wu
Daniel L Gillen
Tatiana B Krasieva
Bruce J Tromberg
William J Pavan
Dave S B Hoon, Department of Translational Molecular Medicine, John Wayne Cancer Institute (JWCI), Pacific Neuroscience Institute, Saint John's Health Center, Providence Health Systems, Santa Monica, CA, 90404, USAFollow
Anand K Ganesan

Document Type

Article

Publication Date

7-1-2017

Publication Title

PLoS Genet

Keywords

Apoptosis; Cell Line, Tumor; Cell Transformation, Neoplastic; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; Humans; Melanocytes; Melanoma; Mutation; Neoplasm Metastasis; Nevus; Proto-Oncogene Proteins B-raf; Signal Transduction; bcl-Associated Death Protein; p21-Activated Kinases; rho GTP-Binding Proteins

Abstract

Genes and pathways that allow cells to cope with oncogene-induced stress represent selective cancer therapeutic targets that remain largely undiscovered. In this study, we identify a RhoJ signaling pathway that is a selective therapeutic target for BRAF mutant cells. RhoJ deletion in BRAF mutant melanocytes modulates the expression of the pro-apoptotic protein BAD as well as genes involved in cellular metabolism, impairing nevus formation, cellular transformation, and metastasis. Short-term treatment of nascent melanoma tumors with PAK inhibitors that block RhoJ signaling halts the growth of BRAF mutant melanoma tumors in vivo and induces apoptosis in melanoma cells in vitro via a BAD-dependent mechanism. As up to 50% of BRAF mutant human melanomas express high levels of RhoJ, these studies nominate the RhoJ-BAD signaling network as a therapeutic vulnerability for fledgling BRAF mutant human tumors.

Clinical Institute

Cancer

Department

Oncology

Recommended Citation

Ruiz, Rolando; Jahid, Sohail; Harris, Melissa; Marzese, Diego M; Espitia, Francisco; Vasudeva, Priya; Chen, Chi-Fen; de Feraudy, Sebastien; Wu, Jie; Gillen, Daniel L; Krasieva, Tatiana B; Tromberg, Bruce J; Pavan, William J; Hoon, Dave S B; and Ganesan, Anand K, "The RhoJ-BAD signaling network: An Achilles' heel for BRAF mutant melanomas." (2017). Articles, Abstracts, and Reports. 2310.
https://digitalcommons.providence.org/publications/2310